There are many signal transduction systems in cells which are functionally linked to each other to control the proliferation, growth, metastasis and apoptosis of cells (Nature Reviews Cancer 5, 689, 2005). The breakdown of the intracellular controlling system by genetic and environmental factors causes abnormal amplification or destruction of the signal transduction system leading to tumor cell generation (Cell 100, 57, 2000).
Protein tyrosine kinases play important roles in such cellular regulation (Nature Reviews Drug Discovery 3, 993, 2004), and their abnormal expression or mutation has been observed in cancer cells. The protein tyrosine kinase is an enzyme which catalyzes the transportation of phosphate groups from ATP to tyrosines located on protein substrates. Many growth factor receptor proteins function as tyrosine kinases to transport cellular signals. The interaction between growth factors and their receptors normally controls the cellular growth, but abnormal signal transduction caused by the mutation or overexpression of any of the receptors often induces tumor cells and cancers.
Protein tyrosine kinases have been classified into many families in accordance with their growth factor types, and epithelial cell growth factor (EGF)-related EGF receptor (EGFR) tyrosine kinase, in particular, have been intensely studied (Nature Reviews Cancer 5, 341, 2005). An EGFR tyrosine kinase is composed of a receptor and tyrosine kinase, and delivers extracellular signals to cell nucleus through the cellular membrane. Various EGFR tyrosine kinases are classified based on their structural differences into EGFR (Erb-B1), Erb-B2, Erb-B3 and Erb-B4, each of which can form a homodimer- or heterodimer-signal delivery complex. Also, the overexpression of more than one of such heterodimers is often observed in malignant cells. In addition, it is known that both EGFR and Erb-B2 significantly contribute to the formation of heterodimer-signal delivery complexes.
Several drugs as small molecules for the inhibition of EGFR tyrosine kinases have been developed, e.g., Gefitinib, Erlotinib, Lapatinib, and others. Gefitinib or Erlotinib selectively and reversibly inhibits EGFR, and Lapatinib reversibly inhibits both EGFR and Erb-B2, thereby arresting the growth of tumors to significantly extend the life time of the patient or to provide therapeutic advantages.
The small-molecule signal transfer inhibitors including EGFR tyrosine kinases have a common structural feature of quinazoline moiety, and tyrosine kinase inhibitors having quinazoline moiety are disclosed in International Publication Nos. WO 99/006396, WO 99/006378, WO 97/038983, WO 2000/031048, WO 98/050038, WO 99/024037, WO 2000/006555, WO 2001/098277, WO 2003/045939, WO 2003/049740 and WO 2005/012290; U.S. Pat. Nos. 7,019,012 and 6,225,318; and European Patent Nos. 0787722, 0387063 and 1292591.
Meanwhile, it has been well known that the development of resistance to a particular drug used causes lowering of the activity of the drug. For example, it has been reported that Gefitinib or Erlotinib generates an EGFR T790M mutant, a secondary mutation, and also that about half of the patients administered with Gefitinib or Erlotinib develop the resistance to Gefitinib or Erlotinib, and that such a drug provides no substantial clinical effect for EGFR T790M variation patients (Public Library of Science Medicine, 2(3), 225, 2005, Cancer Res, 67(24), 11924, 2007).
In this connection, it has been recently found that irreversible inhibitors to an EGFR target are more advantageous in overcoming the problem of the resistance development, as compared to the conventional reversible inhibitors such as Gefitinib and Erlotinib (Cancer Cell 12, 81, 2007, Bioorganic & Medicinal Chemistry 16, 3482, 2008). For example, irreversible inhibitors such as BIBW-2992 (British Journal of Cancer 98, 80, 2008), HKI-272 (Cancer Research 64, 3958, 2004) and AV-412 (Cancer Sci. 98(12), 1977, 2007) have been developed and are currently in the clinical stage. The structures of the irreversible inhibitors are shown below:

The compounds shown above share a common structural feature of having an acrylamide functional group at the position C-6 of the quinazoline or cyanoquinoline residue, which form a covalent bond with Cystein773 (Cys773) positioned at an ATP domain of EGFR, thereby irreversibly blocking the autophosphorylation of EGFR and efficiently inhibiting the signal transfer of cancer cells (Proc. Natl. Acad. Dci. U.S.A. 95, 12022, 1998). They exhibit higher in vitro and in vivo inhibitory activities as compared with the conventional reversible inhibitors (J. Med. Chem. 42, 1803, 1999).
International Patent Publication WO 2008/032039 filed by the authors of the above literature has disclosed a novel anticancer compound having another acrylamide substituent at the position C-6 of quinazoline which shows an improved inhibition activity against EGFR tyrosine kinases.
Accordingly, there has been a continued need to develop a novel drug that has improved activity against EGFR tyrosine kinase mutants, which can effectively inhibit the development of drug-resistance induced by EGFR tyrosine kinase mutants, and while causing no adverse side effects.